This application is for a Midcareer Investigator Award in Patient-Oriented research (K24). It is intended to provide support for Roy Weiss as a clinical investigator to devote focused time for patient orientated research and to act as a mentor for beginning clinical investigators. Dr. Weiss' accomplishments as a clinical investigator and mentor for medical students, residents and fellows make this goal realistic. The research plan is to investigate the role of nuclear cofactors regulating thyroid physiology and disease in man. Thyroid hormone (TH) is essential for normal growth and development as well as maintenance of metabolic activity in the adult. TH action is mediated by intranuclear thyroid hormone receptors (TRs) which regulate the transcription of hormone responsive genes. Coregulators are nuclear proteins which interact with liganded or unliganded nuclear receptors to further modulate the transcription of TR targeted genes. The coregulators may either be corepressors, which inhibit transcription in the absence of TH, or coactivators which stimulate transcriptional activation of the liganded TR. The hypothesis guiding the proposed studies is that defects in cofactors or TRs involved in the mediation of TH action are responsible for the manifestation of diseases of thyroid hormone responsiveness, namely, resistance to TH (RTH) and hypersensitivity to TH. It is proposed to: (1) search in vivo for subtle resistance to glucocorticoids and sex hormones in patients with RTH with and without TR mutations. Identification of such defects will help define the in vivo function of specific cofactors in man. (2) Determine if variability in the phenotype of RTH is due to differences in cofactors that modulate TH action. (3) Determine the cause for hypersensitivity to TH. This will allow clinicians to better identify factors influencing thyroid function.